Metabolic disease is linked to obesity - especially mid-life obesity - a persistent problem in our society. An unexplained connection exists between type 2 diabetes mellitus and neurologic disorders, such as vascular dementia (VaD) and Alzheimer's disease (AD). The biological mechanism underlying this link is not known. As our population demographics shift towards an older average age, the potential confluence of obesity, diabetes and age related neurological dysfunction represents a potential public health disaster. The form of dementia afflicting individuals with a history of obesity and diabetes combines vascular pathology, strokes and AD related neuropathology, including amyloid deposits. It is not known if amyloid, either in the brain parenchyma or deposited within the cerebrovasculature, causes the vascular pathology or if some other aspect of diabetes and obesity is reponsible. This proposal grew out of the possibility that this connection may be related to leptin resistance. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor, which is expressed throughout the brain. Obese individuals are resistant to leptin. In preliminary experiments, we discovered that leptin is a strong regulator of ?-secretase, particularly PS1 expression, at the mRNA level. To investigate this problem, we created a line of knock-in mice that become rapidly obese and diabetic, and develop amyloid pathology with increasing age. The most remarkable feature of this unique mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and displays a profound cognitive impairment. This mouse line does not overexpress disease related proteins or use artificial promoter systems, making it an ideal system for the study of how aberant gene regulation in metabolic disease can influence brain pathology. We believe that we have created a mouse model of VaD, an understudied neurological disorder with limited treatment options. We propose to use our unique db/AD model to determine the mechanistic connection between aberrant leptin signaling and the development of aneurysms, strokes, and other aspects of cerebrovascular pathology. We will track the development of pathology longitudinally using state-of-the-art magnetic resonance imaging, combined with two approaches currently in human clinical trials to treat dementia. Since these approaches have been shown to have a good safety profile in human trials, the clinical implications for the outcome of this study are significant. The major strengths of this proposal are the use of a novel mouse model with unique features, and an innovative approach to determine the mechanism driving the development of pathology. This project has the potential to significantly advance our understanding of the major underlying causes of VaD, and has significant implications for the treatment and prevention of age-related cerebrovascular disease.